The color of human skin is determined by the amount and the type of melanin produced by specialized cells, melanocytes, which are located in the basal layers of skin. Melanin, one of the most widely distributed natural pigments, is a homogeneous polyphenol-like biopolymer with a complex structure and color varying from brown to black (eumelanin) and red to yellow (pheomelanin) (Prota G. Med. Res. Rev. 1988, 8, 525-556). In human skin, melanin is believed to act as a protective agent against ultraviolet radiation. As such, people living close to equator have darker skin than those living in areas away from the equator.
Overproduction of melanin can causes different types of abnormal skin color, hair color, and other dermatological disorders, such as melasma, age spots and sites of actinic damage. Melanin is produced through a series of oxidative reactions and polymerization steps starting with the amino acid tyrosine. Tyrosinase (EC1.14.18.1), a type III, copper-containing enzyme catalyzes two initial reactions in the production of melanin: 1) the ortho-hydroxylation of L-tyrosine by monophenolase action, and 2) the oxidation of 3,4-dihydroxyphenylalanine (L-DOPA)→o-dopaquinone by diphenolase action. The later oxidation step is much more rapid than the former, thus, the hydroxylation of tyrosine is considered to be the rate-determining step in melanin biosynthesis. Subsequent conversion of o-dopaquinone to melanin occurs through a series of enzymatic and non-enzymatic polymerization reactions. Other enzymes, such as dopachrome tautomerase (Tyrosinase Related Protein 2; TRP-2) and dihydroxyindole carboxylic acid (DICHA) oxidase (Tyrosinase Related Protein 1; TRP-1) are also involved in the process of the biosynthesis of melanin. Since tyrosinase plays the key role in the process of melanin production, inhibitors of this enzyme are often used as skin-whitening agents (Mosher et al. In Dermatology in General Medicine, 1983, 205-125, Fitzpatrick T. B., Eisen A. Z., Wolff K., Freedberg I. M., Austern K. F. (eds), Mc-Graw-Hill, New York; Maeda K., Fukuda M, In vitro effectiveness of several whitening cosmetic components in human melanocytes. J. Soc. Cosmet, Chem. 1991, 42, 361-368).
A number of naturally occurring, as well as, synthetic tyrosinase inhibitors have been described in the literature. The majority of compounds comprise a phenol structure. These compounds act as metal chelating agents (Kojima et al. Biol. Pharma. Bull. 1995, 18, 1076-1078; Seo et al. J. Agric. Food Chem. 2003, 51, 2837-2853; Fu et al. J. Agric. Food Chem. 2003, 53, 7408-7414; Kim, Y.-J.; Uyama, H. Cell. Mol. Life Sci. 2005, 62, 1707-1723 and references cited therein). A pharmaceutical product containing hydroquinone (2-4%) is moderately efficacious, but hydroquinone is considered to be cytotoxic to melanocytes and potentially mutagenic to mammalian cells. Unfortunately, several purportedly active agents, e.g., arbutrin and kojic acid, among others have not been demonstrated yet to be clinically efficacious when critically analyzed in carefully controlled studies (Frenk, E. In Melasma: New Approaches to Treatment; Martin Dunitz: London, 1995, 9-15; Dooley, T. P. In: Drug Discovery Approaches for Developing Cosmeceuticals: Advanced Skin Care and Cosmetic Products; Hori, W., Ed.; International business communications: Southborough, M A, 1997; Dooley, T. P. J. Dermatol. Treat. 1997, 7, 188-200).
Many tyrosinase inhibitors are resorcinol derivatives or polyphenol derivatives of flavonoids or of trans-stilbene, such as resveratrol or its derivatives. These types of compounds are known to form strong chelates with metal ions. (Seo et al. J. Agric. Food Chem. 2003, 51, 2837-2853; Fu et al. J. Agric. Food Chem. 2003, 53, 7408-7414; Kim, Y.-J.; Uyama, H. Cell. Mol. Life Sci. 2005, 62, 1707-1723 and references cited therein; Lerch, K. In: Metal ions in Biological Systems, pp. 143-186; Sigel, H., Ed.; Marcel Dekker, N Y, 1981; Wilcox et al. In: Substrate analogue binding to the coupled binuclear copper active site in tyrosinase, J. Am. Chem. Soc. 1985, 107, 4015-4027; Sanchez-Ferrer et al. Biochim. Biophys. Acta 1995, 1247, 1-11; Decker et al. Angew. Chem. Int. Ed. 2000, 39. 1591-1595; Decker et al. Angew. Chem. Int. Ed. 2006, 45. 4546-4550; Briganti et al. Pigment Cell Res. 2003, 16, 101-110). Several compounds based on the resorcinol moiety have been used as tyrosinase inhibitors, see: JP 2008-056651 A; JP 2000-095721 A; US 2005/0267047A1; U.S. Pat. No. 5,339,785; U.S. Pat. No. 6,093,836; US 2008/0032938 A1; U.S. Pat. No. 7,282,592 B2; U.S. Pat. No. 7,339,076 B1; U.S. Pat. No. 5,880,314; U.S. Pat. No. 6,852,310 B2; U.S. Pat. No. 6,077,503; US 2005/0271608 A1; U.S. Pat. No. 5,523,421; US 2007/0098655 A1; US 2005/0267047 A1.
Although many compounds have been reported as potent tyrosinase inhibitors, very few of them have shown skin-whitener properties. Additionally, most of these agents were found either to be toxic, or shown to have adverse side effects in humans. As such, the search for new natural products or synthetic compounds having potent tyrosinase inhibitory activity with low cytotoxicity continues.